This invention concerns a method for treating cancer in patients having deficiency in p53 tumor suppressor gene.
Progression through the cell cycle is controlled by the combined effects of kinases, phosphatases and inhibitory proteins mediated by protein partnering and positive- and negative-acting phosphorylation. The cyclin D1-cdk4-pRb pathway is activated in G1 and initiates progression towards S-phase (DelSal et al. (1996) Critical Rev. in Oncogen. 7:127-142).
Cell cycle progression is characterized by checkpoints where the cell determines whether previous steps have been successfully completed before moving forward. The p53 network serves as a molecular sensor for the G1 checkpoint and monitors DNA damage, nucleotide pool levels, mitotic spindle status and genotoxic stress (Luo et al. (1995) Nature 375:159-161; and Agarwal et al. (1998) J. Biol. Chem. 273:1-4). Additionally, the p53 network regulates cell cycle progression, programmed cell death, replicative senescense and possibly differentiation. In the DNA damage pathway (Kastan et al. (1991) Cancer Res. 51:6304-6311), p53 increases in amount via protein stabilization and transcriptionally activates several genes. Among other events, induction of p53 leads to transcriptional activation of the cyclin dependent kinase inhibitor, p21, which in turn, causes hypophosphorylation of the retinoblastoma protein (Rb), increased binding of Rb to the transcription factor E2F and reduced expression of S-phase specific genes. In the absence of the latter gene products, a G1/S cell cycle arrest ensues. Increases in p53 can either promote apoptosis or G1 arrest depending on the genotype of the cell and the nature of the cellular insult.
Loss of wild-type p53 (wt-p53) function generally leads to uncontrolled cell cycling and replication, inefficient DNA repair, selective growth advantage and, hence, tumor formation. In fact, the p53 gene is mutated in more than 50% of tumors (Beroud et al. (1996) Nucl. Acids Res. 24:147-150).
This invention relates to a method for treating cancer in patients having a deficiency in p53 tumor suppressor gene function. More particularly, the invention provides a method for treating cancer, e.g., preferably a solid tumor, which includes administering to a patient suffering therefrom a therapeutically effective amount of a polyamine of the formula: 
wherein:
R1, R2, R3, R4, R5 and R6 independently are hydrogen or C1-C12 alkyl; m, n and p are independently integers from 3 to 6;
or a pharmaceutically acceptable salt thereof, provided at least one of R1, R2, R5 and R6 is C1-C12 alkyl, in combination with at least one anticancer agent in unit dosage form.
The method preferably is carried out employing a polyamine of the above formula wherein R1 and R6 both are C1-C6 alkyl, especially ethyl, and R2, R3, R4 and R5 are hydrogen. The method is ideally carried out utilizing a polyamine of the above formula where n, m and p independently are 3 or 4.
A particularly valuable compound employed in the method of the invention is the polyamine where m, n and p are 3. This compound is known as bis-ethylnorspermine or N1,N11-diethylnorspermine (DENSPM).
The method of treating cancer of the present invention involves administering a therapeutically effective amount of a polyamine as above defined in combination with an anticancer agent in unit dosage form. Anticancer agents include, but are not limited to, cisplatin, carboplatin, camptothecins, doxorubicin, cyclophosphamide, or etoposide.
Treatment of the patient may be carried out by administering the polyamine and the anticancer agent concurrently but in separate unit dosage forms, preferably by parenteral administration. Alternatively, the polyamine and the anticancer agents may be administered together in a so-called xe2x80x9ccocktailxe2x80x9d. The method of the present invention for treating cancer preferably is used in treating solid tumors, for example, non-small cell lung carcinoma, prostate carcinoma, renal carcinoma, colon carcinoma, ovarian carcinoma, pancreatic carcinoma, and melanoma.
A second aspect of the invention provides an in-vitro method of selecting patients for cancer treatment with a polyamine as defined above including the steps of isolating tumor cells from the patients; determining whether or not the tumor cells are deficient in p53 tumor suppressor gene function; and treating patients having tumors deficient in p53 tumor suppressor gene with a polyamine as above defined. Additionally, the invention provides a method of treating a tumor in a mammal and a method of inducing tumor cell apoptosis.